Barbara L. Kroner

Standards for epidemiologic studies and surveillance of epilepsy

Worldwide, about 65 million people are estimated to have epilepsy. Epidemiologic studies are necessary to define the full public health burden of epilepsy; to set public health and health care priorities; to provide information needed for prevention, early detection, and treatment; to identify education and service needs; and to promote effective health care and support programs for people with epilepsy. However, different definitions and epidemiologic methods complicate the tasks of these studies and their interpretations and comparisons. The purpose of this document is to promote consistency in definitions and methods in an effort to enhance future population‐based epidemiologic studies, facilitate comparison between populations, and encourage the collection of data useful for the promotion of public health. We discuss: (1) conceptual and operational definitions of epilepsy, (2) data resources and recommended data elements, and (3) methods and analyses appropriate for epidemiologic studies or the surveillance of epilepsy. Variations in these are considered, taking into account differing resource availability and needs among countries and differing purposes among studies.

The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty‐five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high‐ or low‐responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35–62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11–21%) corresponding to a relative risk of 3.2 (95% CI 2.1–4.9). Immune‐tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.

Quality‐of‐life differences between prophylactic and on‐demand factor replacement therapy in European haemophilia patients

The European Study on the Clinical Outcomes and Resource Utilization associated with Haemophilia Care was designed to compare various health outcomes associated with on‐demand and prophylactic factor substitution methods in European haemophilia patients. While the primary objective of this research is to conduct an economic analysis, an important component of this study is to evaluate quality‐of‐life differences that may exist between patients who utilize these two styles of therapy. Quality‐of‐life research has emerged as a primary measure of health outcomes because it allows the augmentation of traditional clinical indicators of health with data gathered from the patients perspective. A total of 1033 haemophilia patients from 16 European haemophilia treatment centres were enrolled in this study. The SF‐36, a multidimensional quality‐of‐life instrument, was administered to all participants. This instrument measures eight health‐related quality‐of‐life dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. All haemophilia subjects enrolled in the study scored significantly lower than the population normative means in the three physical dimensions and in the general health dimension. HIV‐negative haemophiliac subjects differed significantly by factor substitution type in a multivariate analysis examining all eight health dimensions. Univariate analyses testing each dimension separately indicated that patients treated prophylactically reported significantly less bodily pain, better general health, and scored significantly higher in the physical functioning, mental health, and social functioning dimensions. While these results suggest that health‐related quality‐of‐life may be better for haemophilia patients treated prophylactically, future prospective studies that gather periodic quality‐of‐life data over time should be conducted.

Clinical outcomes and resource utilization associated with haemophilia care in Europe

We conducted a multicentre, cross‐ sectional study of 1042 haemophilia subjects across Europe to compare various health outcomes associated with on‐demand vs. prophylactic factor‐substitution therapy. Demographic, medical history, and healthcare resource utilization data were analysed along with the number of bleeding events over the past 6 months. Treatment‐cost data were also examined to provide preliminary information for future economic studies. A logistic regression analysis, controlling for other statistically significant covariates, showed that patients treated on demand were 3.4 times more likely to have had a joint bleed over the previous 6 months than those treated with prophylaxis. Multiple regression analyses further confirmed these findings, because on‐demand subjects had, on average, 5.15 more joint bleeds over the reporting period than patients treated with prophylaxis. Notably, these findings were even more dramatic for younger haemophilia patients when our study sample was stratified by age. Due to the high cost of factor replacement, healthcare costs were significantly higher for subjects treated prophylactically. While hospital costs for prophylaxis subjects were, on average, lower, statistically significant cost savings for prophylactic subjects were not noted. These results suggest that clinicians and health policy decision‐makers should consider the advantages of prophylactic therapy for haemophilia patients in formulating treatment protocols and allocating health resources.

Comparison of the International Immune Tolerance Registry and the North American Immune Tolerance Registry

Two immune tolerance registries – the International Immune Tolerance Study Group (ITSG) and North American Immune Tolerance Study (NAITS) – are compared and findings from combined data reported. The registries differed with respect to data collection tools, location, host and environmental factors, start date distribution and treatment products. The success and failure rates were similar in the two studies. There was a highly significant association between maximum historical titre and immune tolerance success; the success rate decreased as the historical titre increased. There was a significant association between inhibitor titre immediately prior to treatment and the probability for treatment success, and between outcome and time from diagnosis to treatment in the ITSG (of borderline significance in the NAITS). There was a significant association between outcome and dose, though the direction of the associations was not the same. In the ITSG, success was associated with doses greater than or equal to 200 IU/kg/day, while in the NAITS, greater success was observed with doses of less than 50 IU/kg/day. There was no association between outcome and treatment product. Data from the two registries were combined to produce a table for calculating the chance of successful treatment by historical titre, pretreatment titre, and dose.

SCN8A encephalopathy: Research progress and prospects

On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.

Impact of Image Analysis Methodology on Diagnostic and Surgical Classification of Patients With Thoracic Aortic Aneurysms

BACKGROUND For patients with thoracic aortic aneurysms (TAA), aortic size on imaging is widely used to guide clinical decision making. This study examined the impact of methodological variance on aortic quantification. METHODS We studied enrollees in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. Aortic size on computed tomography was quantified by 2 linear methods; cross-sectional dimensions in axial (AX) and double oblique (DO) plane. Calculated area was compared to planimetry. Established cutoffs (area/height>10 cm2/m, diameter≥5 cm) for prophylactic TAA repair were used to compare surgical eligibility by each method. RESULTS Fifty subjects were studied. Aortic size differed between AX and DO at all locations (p≤0.001), with magnitude greatest at the sinotubular junction (4.8±1.1 vs 4.0±1.0 cm, p<0.001). The difference between AX and DO correlated with aortic angular displacement (r=0.37, p<0.01), which was threefold larger at the sinotubular junction (37±12 degrees) than the ascending aorta (12±5 degrees; p<0.001). At all locations, aortic area calculated using DO yielded smaller differences with planimetry than AX (p<0.05). DO and planimetry yielded equal prevalence (24%) of subjects eligible for prophylactic TAA repair based on area-height cutoff, whereas AX prevalence was higher (44%; p=0.006). Using a linear cutoff, AX yielded over a twofold greater prevalence of surgically eligible subjects (56%) than did DO (24%; p<0.001). CONCLUSIONS Established linear methods for aortic measurement yield different results that impact surgical eligibility. DO yielded improved agreement with planimetry and differed with AX in proportion to aortic geometric obliquity. Findings support DO measurements for imaging evaluation of subjects with TAA.

Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C.

Summary.  Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.

New Incidence, Prevalence, and Survival of Aicardi Syndrome From 408 Cases

We sought to determine the incidence, prevalence, and life expectancy of Aicardi syndrome from 408 cases compiled from multiple international sources. Last known age ranged from less than 1 month to 42 years. The incidence rates per live births for the United States and The Netherlands were 1 per 105 000 and 1 per 93 000, respectively. The prevalence in the United States is greater than 853 cases, and the worldwide estimate is several thousand. Forty-five cases were deceased (age range, 1 month to 33 years), and the risk of death peaked at age 16. The probability of survival at 27 years of age was 0.62 (95% CI, 0.47-0.77). The risk of death by age follows other congenital neurological disorders with a wide range in severity of functional disability. The longer life expectancy found in our study hints at a higher functioning capacity in Aicardi syndrome and may inform counseling to families.

The National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): results from phase I and scientific opportunities in phase II.

BACKGROUND Genetically triggered thoracic aortic conditions (GenTACs) represent an important problem for patients and their families. Accordingly, the National Heart, Lung, and Blood Institute established the first phase of its national GenTAC Registry in 2006. ENROLLMENT AND DIAGNOSES Between 2007 and 2010, 6 enrolling centers established the GenTAC I Registry consisting of 2,046 patients (Marfan syndrome 576 [28.2%], bicuspid aortic valve disease 504 [24.6%], aneurysm or dissection age <50 years 369 [18%], and others). Biologic samples for DNA analyses (white blood cells or saliva) are available in 97%, and stored plasma is available in 60% of enrollees. RESULTS Initial scientific inquiry using the GenTAC Registry has included validation studies of genetic causes for aortic syndromes, potential usefulness of transforming growth factor beta (TGFB) blood levels in Marfan subjects, and current surgical approaches to ascending aortic conditions. FUTURE OPPORTUNITY The second phase of GenTAC will allow biannual follow-up of GenTAC I enrollees for up to 9 years, enrollment of an additional 1,500 subjects, further integration of imaging findings with clinical and genetic data through utilization of an imaging core laboratory, important validation of phenotype-genotype correlations through a phenotyping core laboratory, and integration of a scientific advisory committee to help define the full range and depth of the Registrys scientific capabilities. The registry resources are available to the external scientific community through an application process accessible at https://gentac.rti.org.